Paxil-CR

SIDE EFFECTS

The information included under the “Adverse Findings
Observed in Short-Term, Placebo-Controlled Trials With PAXIL CR” subsection of
ADVERSE REACTIONS is based on data from 11 placebo-controlled clinical trials.
Three of these studies were conducted in patients with major depressive
disorder, 3 studies were done in patients with panic disorder, 1 study was
conducted in patients with social anxiety disorder, and 4 studies were done in
female patients with PMDD. Two of the studies in major depressive disorder,
which enrolled patients in the age range 18 to 65 years, are pooled.
Information from a third study of major depressive disorder, which focused on
elderly patients (60 to 88 years), is presented separately as is the
information from the panic disorder studies and the information from the PMDD
studies. Information on additional adverse events associated with PAXIL CR and
the immediate-release formulation of paroxetine hydrochloride is included in a
separate subsection (see Other Events Observed During the Clinical
Development of Paroxetine).

Adverse Events Associated With Discontinuation of
Treatment: Major Depressive Disorder

Ten percent (21/212) of patients treated with PAXIL CR
discontinued treatment due to an adverse event in a pool of 2 studies of
patients with major depressive disorder. The most common events ( ≥ 1%)
associated with discontinuation and considered to be drug related (i.e., those
events associated with dropout at a rate approximately twice or greater for
PAXIL CR compared to placebo) included the following:

PAXIL CR
(n = 212)

Placebo
(n = 211)

Nausea

3.7%

0.5%

Asthenia

1.9%

0.5%

Dizziness

1.4%

0.0%

Somnolence

1.4%

0.0%

In a placebo-controlled study
of elderly patients with major depressive disorder, 13% (13/104) of patients
treated with PAXIL CR discontinued due to an adverse event. Events meeting the
above criteria included the following:

PAXIL CR
(n = 104)

Placebo
(n = 109)

Nausea

2.9%

0.0%

Headache

1.9%

0.9%

Depression

1.9%

0.0%

LFT’s abnormal

1.9%

0.0%

Panic Disorder

Eleven percent (50/444) of
patients treated with PAXIL CR in panic disorder studies discontinued treatment
due to an adverse event. Events meeting the above criteria included the
following:

PAXIL CR
(n = 444)

Placebo
(n = 445)

Nausea

2.9%

0.4%

Insomnia

1.8%

0.0%

Headache

1.4%

0.2%

Asthenia

1.1%

0.0%

Social Anxiety Disorder

Three percent (5/186) of
patients treated with PAXIL CR in the social anxiety disorder study
discontinued treatment due to an adverse event. Events meeting the above
criteria included the following:

PAXIL CR
(n = 186)

Placebo
(n = 184)

Nausea

2.2%

0.5%

Headache

1.6%

0.5%

Diarrhea

1.1%

0.5%

Premenstrual Dysphoric Disorder

Spontaneously reported adverse
events were monitored in studies of both continuous and intermittent dosing of
PAXIL CR in the treatment of PMDD. Generally, there were few differences in the
adverse event profiles of the 2 dosing regimens. Thirteen percent (88/681) of
patients treated with PAXIL CR in PMDD studies of continuous dosing
discontinued treatment due to an adverse event.

The most common events ( ≥ 1%) associated with
discontinuation in either group treated with PAXIL CR with an incidence rate
that is at least twice that of placebo in PMDD trials that employed a
continuous dosing regimen are shown in the following table. This table also
shows those events that were dose dependent (indicated with an asterisk) as
defined as events having an incidence rate with 25 mg of PAXIL CR that was at
least twice that with 12.5 mg of PAXIL CR (as well as the placebo group).

PAXIL CR 25 mg
(n = 348)

PAXIL CR 12.5 mg
(n = 333)

Placebo
(n = 349)

TOTAL

15%

9.9%

6.3%

Nauseaa

6.0%

2.4%

0.9%

Asthenia

4.9%

3.0%

1.4%

Somnolencea

4.3%

1.8%

0.3%

Insomnia

2.3%

1.5%

0.0%

Concentration Impaireda

2.0%

0.6%

0.3%

Dry moutha

2.0%

0.6%

0.3%

Dizzinessa

1.7%

0.6%

0.6%

Decreased Appetitea

1.4%

0.6%

0.0%

Sweatinga

1.4%

0.0%

0.3%

Tremora

1.4%

0.3%

0.0%

Yawna

1.1%

0.0%

0.0%

Diarrhea

0.9%

1.2%

0.0%

a Events considered to be dose dependent are defined as
events having an incidence rate with 25 mg of PAXIL CR that was at least twice
that with 12.5 mg of PAXIL CR (as well as the placebo group).

Commonly Observed Adverse
Events

Major Depressive Disorder

The most commonly observed
adverse events associated with the use of PAXIL CR in a pool of 2 trials
(incidence of 5.0% or greater and incidence for PAXIL CR at least twice that
for placebo, derived from Table 2) were: Abnormal ejaculation, abnormal vision,
constipation, decreased libido, diarrhea, dizziness, female genital disorders,
nausea, somnolence, sweating, trauma, tremor, and yawning.

Using the same criteria, the
adverse events associated with the use of PAXIL CR in a study of elderly
patients with major depressive disorder were: Abnormal ejaculation,
constipation, decreased appetite, dry mouth, impotence, infection, libido
decreased, sweating, and tremor.

Social Anxiety Disorder

Premenstrual Dysphoric Disorder

The most commonly observed
adverse events associated with the use of PAXIL CR either during continuous
dosing or luteal phase dosing (incidence of 5% or greater and incidence for
PAXIL CR at least twice that for placebo, derived from Table 6) were: Nausea,
asthenia, libido decreased, somnolence, insomnia, female genital disorders,
sweating, dizziness, diarrhea, and constipation.

In the luteal phase dosing PMDD
trial, which employed dosing of 12.5 mg/day or 25 mg/day of PAXIL CR limited to the 2 weeks prior to the onset of
menses over 3 consecutive menstrual cycles, adverse events were evaluated
during the first 14 days of each off-drug phase. When the 3 off-drug phases
were combined, the following adverse events were reported at an incidence of 2%
or greater for PAXIL CR and were at least twice the rate of that reported for
placebo: Infection (5.3% versus 2.5%), depression (2.8% versus 0.8%), insomnia
(2.4% versus 0.8%), sinusitis (2.4% versus 0%), and asthenia (2.0% versus
0.8%).

Incidence In Controlled
Clinical Trials

Table 2 enumerates adverse
events that occurred at an incidence of 1% or more among patients treated with
PAXIL CR, aged 18 to 65, who participated in 2 short-term (12-week)
placebo-controlled trials in major depressive disorder in which patients were
dosed in a range of 25 mg to 62.5 mg/day. Table 3 enumerates adverse events
reported at an incidence of 5% or greater among elderly patients (ages 60 to
88) treated with PAXIL CR who participated in a short-term (12-week)
placebo-controlled trial in major depressive disorder in which patients were
dosed in a range of 12.5 mg to 50 mg/day. Table 4 enumerates adverse events
reported at an incidence of 1% or greater among patients (19 to 72 years)
treated with PAXIL CR who participated in short-term (10-week)
placebo-controlled trials in panic disorder in which patients were dosed in a
range of 12.5 mg to 75 mg/day. Table 5 enumerates adverse events reported at an
incidence of 1% or greater among adult patients treated with PAXIL CR who
participated in a short-term (12-week), double-blind, placebo-controlled trial
in social anxiety disorder in which patients were dosed in a range of 12.5 to
37.5 mg/day. Table 6 enumerates adverse events that occurred at an incidence of
1% or more among patients treated with PAXIL CR who participated in three,
12-week, placebo-controlled trials in PMDD in which patients were dosed at 12.5
mg/day or 25 mg/day and in one 12-week placebo-controlled trial in which
patients were dosed for 2 weeks prior to the onset of menses (luteal phase
dosing) at 12.5 mg/day or 25 mg/day. Reported adverse events were classified
using a standard COSTART-based Dictionary terminology.

The prescriber should be aware
that these figures cannot be used to predict the incidence of side effects in
the course of usual medical practice where patient characteristics and other
factors differ from those that prevailed in the clinical trials. Similarly, the
cited frequencies cannot be compared with figures obtained from other clinical
investigations involving different treatments, uses, and investigators. The
cited figures, however, do provide the prescribing physician with some basis
for estimating the relative contribution of drug and nondrug factors to the
side effect incidence rate in the population studied.

Table 2: Treatment-Emergent Adverse Events Occurring
in ≥ 1% of Patients Treated With PAXIL CR in a Pool of 2 Studies in
Major Depressive Disordera,b

Body System/ Adverse Event

% Reporting Event

PAXIL CR
(n = 212)

Placebo
(n = 211)

Body as a Whole

Headache

27%

20%

Asthenia

14%

9%

Infectionc

8%

5%

Abdominal Pain

7%

4%

Back Pain

5%

3%

Traumad

5%

1%

Paine

3%

1%

Allergic Reactionf

2%

1%

Cardiovascular System

Tachycardia

1%

0%

Vasodilatationg

2%

0%

Digestive System

Nausea

22%

10%

Diarrhea

18%

7%

Dry Mouth

15%

8%

Constipation

10%

4%

Flatulence

6%

4%

Decreased Appetite

4%

2%

Vomiting

2%

1%

Nervous System

Somnolence

22%

8%

Insomnia

17%

9%

Dizziness

14%

4%

Libido Decreased

7%

3%

Tremor

7%

1%

Hypertonia

3%

1%

Paresthesia

3%

1%

Agitation

2%

1%

Confusion

1%

0%

Respiratory System

Yawn

5%

0%

Rhinitis

4%

1%

Cough Increased

2%

1%

Bronchitis

1%

0%

Skin and Appendages

Sweating

6%

2%

Photosensitivity

2%

0%

Special Senses

Abnormal Visionh

5%

1%

Taste Perversion

2%

0%

Urogenital System

Abnormal Ejaculationi,j

26%

1%

Female Genital Disorderi,k

10%

< 1%

Impotencei

5%

3%

Urinary Tract Infection

3%

1%

Menstrual Disorderi

2%

< 1%

Vaginitisi

2%

0%

aAdverse events for which the PAXIL CR
reporting incidence was less than or equal to the placebo incidence are not
included. These events are: Abnormal dreams, anxiety, arthralgia,
depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, increased appetite,
myalgia, nervousness, pharyngitis, purpura, rash, respiratory disorder,
sinusitis, urinary frequency, and weight gain. b < 1% means greater than zero and less than 1%. c Mostly flu. d A wide variety of injuries with no obvious pattern. e Pain in a variety of locations with no obvious pattern. f Most frequently seasonal allergic symptoms. g Usually flushing. hMostly blurred vision. iBased on the number of males or females. j Mostly anorgasmia or delayed ejaculation. k Mostly anorgasmia or delayed orgasm.

Table 3: Treatment-Emergent
Adverse Events Occurring in ≥ 5%
of Patients Treated With PAXIL CR in a Study of Elderly Patients With Major
Depressive Disordera,b

Body System/ Adverse Event

% Reporting Event

PAXIL CR
(n = 104)

Placebo
(n = 109)

Body as a Whole

Headache

17%

13%

Asthenia

15%

14%

Trauma

8%

5%

Infection

6%

2%

Digestive System

Dry Mouth

18%

7%

Diarrhea

15%

9%

Constipation

13%

5%

Dyspepsia

13%

10%

Decreased Appetite

12%

5%

Flatulence

8%

7%

Nervous System

Somnolence

21%

12%

Insomnia

10%

8%

Dizziness

9%

5%

Libido Decreased

8%

< 1%

Tremor

7%

0%

Skin and Appendages

Sweating

10%

< 1%

Urogenital System

Abnormal Ejaculationc,d

17%

3%

Impotencec

9%

3%

a Adverse events for which the PAXIL CR
reporting incidence was less than or equal to the placebo incidence are not
included. These events are nausea and respiratory disorder. b < 1% means greater than zero and less than 1%. c Based on the number of males. d Mostly anorgasmia or delayed ejaculation.

a Adverse events for which the reporting rate
for PAXIL CR was less than or equal to the placebo rate are not included. These
events are: Dysmenorrhea, flatulence, gastroenteritis, hypertonia, infection,
pain, pharyngitis, rash, respiratory disorder, rhinitis, and vomiting. b < 1% means greater than zero and less than 1%. c Various physical injuries. d Most frequently seasonal allergic symptoms. e Mostly blurred vision. f Based on the number of male patients. g Mostly anorgasmia or delayed ejaculation. h Based on the number of female patients. i Mostly anorgasmia or difficulty achieving orgasm.

a Adverse events for which the reporting rate
of PAXIL CR was less than or equal to the placebo rate are not included. These
events for continuous dosing are: Abdominal pain, back pain, pain, trauma,
weight gain, myalgia, pharyngitis, respiratory disorder, rhinitis, sinusitis,
pruritus, dysmenorrhea, menstrual disorder, urinary tract infection, and
vomiting. The events for luteal phase dosing are: Allergic reaction, back pain,
headache, infection, pain, trauma, myalgia, anxiety, pharyngitis, respiratory
disorder, cystitis, and dysmenorrhea. b < 1% means greater than zero and less than 1%. c The luteal phase and continuous dosing PMDD trials were not
designed for making direct comparisons between the 2 dosing regimens.
Therefore, a comparison between the 2 dosing regimens of the PMDD trials of
incidence rates shown in Table 6 should be avoided. d Mostly anorgasmia or difficulty achieving orgasm.

Dose Dependency of Adverse
Events

Table 7 shows results in PMDD
trials of common adverse events, defined as events with an incidence of
≥ 1% with 25 mg of PAXIL CR that was at least twice that with 12.5 mg of
PAXIL CR and with placebo.

Table 7: Incidence of Common Adverse Events in
Placebo, 12.5 mg, and 25 mg of PAXIL CR in a Pool of 3 Fixed-Dose PMDD Trials

PAXIL CR 25 mg
(n = 348)

PAXIL CR 12.5 mg
(n = 333)

Placebo
(n = 349)

Common Adverse Event

Sweating

8.9%

4.2%

0.9%

Tremor

6.0%

1.5%

0.3%

Concentration Impaired

4.3%

1.5%

0.6%

Yawn

3.2%

0.9%

0.3%

Paresthesia

1.4%

0.3%

0.3%

Hyperkinesia

1.1%

0.3%

0.0%

Vaginitis

1.1%

0.3%

0.3%

A comparison of adverse event rates in a fixed-dose study
comparing immediate-release paroxetine with placebo in the treatment of major
depressive disorder revealed a clear dose dependency for some of the more
common adverse events associated with the use of immediate-release paroxetine.

Male and Female Sexual
Dysfunction With SSRIs

Although changes in sexual
desire, sexual performance, and sexual satisfaction often occur as
manifestations of a psychiatric disorder, they may also be a consequence of
pharmacologic treatment. In particular, some evidence suggests that SSRIs can
cause such untoward sexual experiences.

Reliable estimates of the
incidence and severity of untoward experiences involving sexual desire, performance,
and satisfaction are difficult to obtain; however, in part because patients and
physicians may be reluctant to discuss them. Accordingly, estimates of the
incidence of untoward sexual experience and performance cited in product
labeling, are likely to underestimate their actual incidence.

The percentage of patients
reporting symptoms of sexual dysfunction in the pool of 2 placebo-controlled
trials in nonelderly patients with major depressive disorder, in the pool of 3
placebo-controlled trials in patients with panic disorder, in the
placebo-controlled trial in patients with social anxiety disorder, and in the
intermittent dosing and the pool of 3 placebo-controlled continuous dosing
trials in female patients with PMDD are as follows:

Major Depressive Disorder

Panic Disorder

Social Anxiety Disorder

PMDD Continuous Dosing

PMDD Luteal Phase Dosing

PAXIL CR

Placebo

PAXIL CR

Placebo

PAXIL CR

Placebo

PAXIL CR

Placebo

PAXIL CR

Placebo

n (males)

78

78

162

194

88

97

n/a

n/a

n/a

n/a

Decreased Libido

10%

5%

9%

6%

13%

1%

n/a

n/a

n/a

n/a

Ejaculatory Disturbance

26%

1%

27%

3%

15%

1%

n/a

n/a

n/a

n/a

Impotence

5%

3%

10%

1%

9%

0%

n/a

n/a

n/a

n/a

n (females)

134

133

282

251

98

87

681

349

246

120

Decreased Libido

4%

2%

8%

2%

4%

1%

12%

5%

9%

6%

Orgasmic Disturbance

10%

< 1%

7%

1%

3%

0%

8%

1%

2%

0%

There are no adequate,
controlled studies examining sexual dysfunction with paroxetine treatment.

Paroxetine treatment has been associated
with several cases of priapism. In those cases with a known outcome, patients
recovered without sequelae.

While it is difficult to know
the precise risk of sexual dysfunction associated with the use of SSRIs,
physicians should routinely inquire about such possible side effects.

Weight and Vital Sign Changes

Significant weight loss may be
an undesirable result of treatment with paroxetine for some patients but, on
average, patients in controlled trials with PAXIL CR or the immediate-release
formulation, had minimal weight loss (about 1 pound). No significant changes in
vital signs (systolic and diastolic blood pressure, pulse, and temperature)
were observed in patients treated with PAXIL CR, or immediate-release
paroxetine hydrochloride, in controlled clinical trials.

ECG Changes

In an analysis of ECGs obtained
in 682 patients treated with immediate-release paroxetine and 415 patients
treated with placebo in controlled clinical trials, no clinically significant
changes were seen in the ECGs of either group.

Liver Function Tests

In a pool of 2
placebo-controlled clinical trials, patients treated with PAXIL CR or placebo
exhibited abnormal values on liver function tests at comparable rates. In
particular, the controlled-release paroxetine-versus-placebo comparisons for
alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the
percentage of patients with marked abnormalities.

In a study of elderly patients
with major depressive disorder, 3 of 104 patients treated with PAXIL CR and
none of 109 placebo patients experienced liver transaminase elevations of
potential clinical concern.

Two of the patients treated with PAXIL CR dropped out of
the study due to abnormal liver function tests; the third patient experienced
normalization of transaminase levels with continued treatment. Also, in the
pool of 3 studies of patients with panic disorder, 4 of 444 patients treated
with PAXIL CR and none of 445 placebo patients experienced liver transaminase
elevations of potential clinical concern. Elevations in all 4 patients
decreased substantially after discontinuation of PAXIL CR. The clinical
significance of these findings is unknown.

In placebo-controlled clinical trials with the
immediate-release formulation of paroxetine, patients exhibited abnormal values
on liver function tests at no greater rate than that seen in placebo-treated
patients.

Hallucinations

In pooled clinical trials of immediate-release paroxetine
hydrochloride, hallucinations were observed in 22 of 9,089 patients receiving
drug and in 4 of 3,187 patients receiving placebo.

Other Events Observed During The Clinical Development Of Paroxetine

The following adverse events were reported during the
clinical development of PAXIL CR and/or the clinical development of the
immediate-release formulation of paroxetine.

Adverse events for which frequencies are provided below
occurred in clinical trials with the controlled-release formulation of
paroxetine. During its premarketing assessment in major depressive disorder,
panic disorder, social anxiety disorder, and PMDD, multiple doses of PAXIL CR
were administered to 1,627 patients in phase 3 double-blind, controlled,
outpatient studies. Untoward events associated with this exposure were recorded
by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the
proportion of individuals experiencing adverse events without first grouping
similar types of untoward events into a smaller number of standardized event
categories.

In the tabulations that follow, reported adverse events
were classified using a COSTART-based dictionary. The frequencies presented,
therefore, represent the proportion of the 1,627 patients exposed to PAXIL CR
who experienced an event of the type cited on at least 1 occasion while
receiving PAXIL CR. All reported events are included except those already
listed in Tables 2 through 7 and those events where a drug cause was remote. If
the COSTART term for an event was so general as to be uninformative, it was
deleted or, when possible, replaced with a more informative term. It is
important to emphasize that although the events reported occurred during
treatment with paroxetine, they were not necessarily caused by it.

Events are further categorized by body system and listed
in order of decreasing frequency according to the following definitions:
Frequent adverse events are those occurring on 1 or more occasions in at least
1/100 patients (only those not already listed in the tabulated results from
placebo-controlled trials appear in this listing); infrequent adverse events
are those occurring in 1/100 to 1/1,000 patients; rare events are those
occurring in fewer than 1/1,000 patients.

Adverse events for which frequencies are not provided
occurred during the premarketing assessment of immediate-release paroxetine in
phase 2 and 3 studies of major depressive disorder, obsessive compulsive
disorder, panic disorder, social anxiety disorder, generalized anxiety
disorder, and posttraumatic stress disorder. The conditions and duration of
exposure to immediate-release paroxetine varied greatly and included (in
overlapping categories) open and double-blind studies, uncontrolled and
controlled studies, inpatient and outpatient studies, and fixed-dose and
titration studies. Only those events not previously listed for
controlled-release paroxetine are included. The extent to which these events
may be associated with PAXIL CR is unknown.

Events are listed alphabetically within the respective
body system. Events of major clinical importance are also described in the
PRECAUTIONS section.

Postmarketing Reports

Voluntary reports of adverse events in patients taking
immediate-release paroxetine hydrochloride that have been received since market
introduction and not listed above that may have no causal relationship with the
drug include acute pancreatitis, elevated liver function tests (the most severe
cases were deaths due to liver necrosis, and grossly elevated transaminases
associated with severe liver dysfunction), Guillain-Barré syndrome, Stevens-Johnson
syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH
secretion, symptoms suggestive of prolactinemia and galactorrhea;
extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel
rigidity, dystonia, hypertonia, oculogyric crisis which has been associated
with concomitant use of pimozide; tremor and trismus; status epilepticus, acute
renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis,
eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome
(RLS), ventricular fibrillation, ventricular tachycardia (including torsade de
pointes), thrombocytopenia, hemolytic anemia, events related to impaired
hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia,
and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura)
and premature births in pregnant women. There has been a case report of an
elevated phenytoin level after 4 weeks of immediate-release paroxetine and phenytoin
coadministration. There has been a case report of severe hypotension when
immediate-release paroxetine was added to chronic metoprolol treatment.

Drug Abuse And Dependence

Controlled Substance Class

PAXIL CR is not a controlled substance.

Physical And Psychologic Dependence

PAXIL CR has not been systematically studied in animals
or humans for its potential for abuse, tolerance or physical dependence. While
the clinical trials did not reveal any tendency for any drug-seeking behavior,
these observations were not systematic and it is not possible to predict on the
basis of this limited experience the extent to which a CNS-active drug will be
misused, diverted, and/or abused once marketed. Consequently, patients should
be evaluated carefully for history of drug abuse, and such patients should be
observed closely for signs of misuse or abuse of PAXIL CR (e.g., development of
tolerance, incrementations of dose, drug-seeking behavior).

DRUG INTERACTIONS

Tryptophan

As with other serotoninreuptake inhibitors, an
interaction between paroxetine and tryptophan may occur when they are
coadministered. Adverse experiences, consisting primarily of headache, nausea,
sweating, and dizziness, have been reported when tryptophan was administered to
patients taking immediate-release paroxetine. Consequently, concomitant use of
PAXIL CR with tryptophan is not recommended (see WARNINGS: Serotonin
Syndrome).

Monoamine Oxidase Inhibitors

Pimozide

In a controlled study of healthy volunteers, after
immediate-release paroxetine hydrochloride was titrated to 60 mg daily,
co-administration of a single dose of 2 mg pimozide was associated with mean
increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide
administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6
inhibitory properties of paroxetine. Due to the narrow therapeutic index of
pimozide and its known ability to prolong the QT interval, concomitant use of
pimozide and PAXIL CR is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs,
including paroxetine hydrochloride, and the potential for serotonin syndrome,
caution is advised when PAXIL CR is coadministered with other drugs that may
affect the serotonergic neurotransmitter systems, such as triptans, lithium,
fentanyl, tramadol, or St. John's Wort (see WARNINGS: Serotonin
Syndrome).

The concomitant use of PAXIL CR with MAOIs (including
linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS).
The concomitant use of PAXIL CR with other SSRIs, SNRIs or tryptophan is not
recommended (see PRECAUTIONS: Drug Interactions, Tryptophan).

Thioridazine

Warfarin

Preliminary data suggest that there may be a
pharmacodynamic interaction (that causes an increased bleeding diathesis in the
face of unaltered prothrombin time) between paroxetine and warfarin. Since
there is little clinical experience, the concomitant administration of PAXIL CR
and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs
That Interfere With Hemostasis).

Triptans

There have been rare postmarketing reports of serotonin
syndrome with the use of an SSRI and a triptan. If concomitant use of PAXIL CR
with a triptan is clinically warranted, careful observation of the patient is
advised, particularly during treatment initiation and dose increases (see WARNINGS:
Serotonin Syndrome).

Drugs Affecting Hepatic Metabolism

The metabolism and pharmacokinetics of paroxetine may be
affected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine

Cimetidine inhibits many cytochrome P450 (oxidative)
enzymes. In a study where immediate-release paroxetine (30 mg once daily) was
dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were
increased by approximately 50% during coadministration with oral cimetidine
(300 mg three times daily) for the final week. Therefore, when these drugs are
administered concurrently, dosage adjustment of PAXIL CR after the starting
dose should be guided by clinical effect. The effect of paroxetine on
cimetidine's pharmacokinetics was not studied.

Phenobarbital

Phenobarbital induces many cytochrome P450 (oxidative)
enzymes. When a single oral 30-mg dose of immediate-release paroxetine was
administered at phenobarbital steady state (100 mg once daily for 14 days),
paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
respectively) compared to paroxetine administered alone. The effect of
paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine
exhibits nonlinear pharmacokinetics, the results of this study may not address
the case where the 2 drugs are both being chronically dosed. No initial dosage
adjustment with PAXIL CR is considered necessary when coadministered with
phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin

When a single oral 30-mg dose of immediate-release
paroxetine was administered at phenytoin steady state (300 mg once daily for 14
days), paroxetine AUC and T½ were reduced (by an average of 50% and
35%, respectively) compared to immediate-release paroxetine administered alone.
In a separate study, when a single oral 300-mg dose of phenytoin was
administered at paroxetine steady state (30 mg once daily for 14 days),
phenytoin AUC was slightly reduced (12% on average) compared to phenytoin
administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the
above studies may not address the case where the 2 drugs are both being chronically
dosed. No initial dosage adjustments are considered necessary when PAXIL CR is
coadministered with phenytoin; any subsequent adjustments should be guided by
clinical effect (see ADVERSE REACTIONS: Postmarketing Reports).

Drugs Metabolized by CYP2D6

Many drugs, including most drugs effective in the
treatment of major depressive disorder (paroxetine, other SSRIs, and many
tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other
agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the
activity of this isozyme. In most patients ( > 90%), this CYP2D6 isozyme is
saturated early during paroxetine dosing. In 1 study, daily dosing of
immediate-release paroxetine (20 mg once daily) under steady-state conditions increased
single-dose desipramine (100 mg) Cmax, AUC, and T½ by an average of
approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine
with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily
dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8
mg/day) increased mean plasma concentrations of risperidone approximately
4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and
increased concentrations of the active moiety (the sum of risperidone plus
9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the
pharmacokinetics of atomoxetine has been evaluated when both drugs were at
steady state. In healthy volunteers who were extensive metabolizers of CYP2D6,
paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12
hours. This resulted in increases in steady state atomoxetine AUC values that
were 6-to 8-fold greater and in atomoxetine Cmax values that were 3-to 4-fold
greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine
may be necessary and it is recommended that atomoxetine be initiated at a
reduced dose when given with paroxetine.

Concomitant use of PAXIL CR with other drugs metabolized
by cytochrome CYP2D6 has not been formally studied but may require lower doses
than usually prescribed for either PAXIL CR or the other drug.

Therefore, coadministration of PAXIL CR with other drugs
that are metabolized by this isozyme, including certain drugs effective in the
treatment of major depressive disorder (e.g., nortriptyline, amitriptyline,
imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type
1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that
inhibit this enzyme (e.g., quinidine), should be approached with caution.

However, due to the risk of serious ventricular
arrhythmias and sudden death potentially associated with elevated plasma levels
of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS
and WARNINGS).

Tamoxifen is a pro-drug requiring metabolic activation by
CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma
concentrations of an active metabolite (endoxifen) and hence reduced efficacy
of tamoxifen (see PRECAUTIONS).

Drugs Metabolized by Cytochrome CYP3A4

An in vivo interaction study involving the
coadministration under steady-state conditions of paroxetine and terfenadine, a
substrate for CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics.
In addition, in vitro studies have shown ketoconazole, a potent inhibitor of
CYP3A4 activity, to be at least 100 times more potent than paroxetine as an
inhibitor of the metabolism of several substrates for this enzyme, including
terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the
assumption that the relationship between paroxetine's in vitro Ki and its lack
of effect on terfenadine's in vivo clearance predicts its effect on other
CYP3A4 substrates, paroxetine's extent of inhibition of CYP3A4 activity is not
likely to be of clinical significance.

Tricyclic Antidepressants (TCAs)

Caution is indicated in the coadministration of TCAs with
PAXIL CR, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations
may need to be monitored, and the dose of TCA may need to be reduced, if a TCA
is coadministered with PAXIL CR (see PRECAUTIONS: Drugs Metabolized
by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein

Because paroxetine is highly bound to plasma protein,
administration of PAXIL CR to a patient taking another drug that is highly
protein bound may cause increased free concentrations of the other drug,
potentially resulting in adverse events. Conversely, adverse effects could
result from displacement of paroxetine by other highly bound drugs.

Drugs That Interfere With Hemostasis (e.g., NSAIDs,
Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in
hemostasis. Epidemiological studies of the case-control and cohort design that
have demonstrated an association between use of psychotropic drugs that
interfere with serotonin reuptake and the occurrence of upper gastrointestinal
bleeding have also shown that concurrent use of an NSAID or aspirin may
potentiate this risk of bleeding. Altered anticoagulant effects, including
increased bleeding, have been reported when SSRIs or SNRIs are coadministered
with warfarin. Patients receiving warfarin therapy should be carefully
monitored when paroxetine is initiated or discontinued.

Alcohol

Although paroxetine does not increase the impairment of
mental and motor skills caused by alcohol, patients should be advised to avoid
alcohol while taking PAXIL CR.

Lithium

A multiple-dose study with immediate-release paroxetine
hydrochloride has shown that there is no pharmacokinetic interaction between
paroxetine and lithium carbonate. However, due to the potential for serotonin
syndrome, caution is advised when immediate-release paroxetine hydrochloride is
coadministered with lithium.

Digoxin

The steady-state pharmacokinetics of paroxetine was not
altered when administered with digoxin at steady state. Mean digoxin AUC at
steady state decreased by 15% in the presence of paroxetine. Since there is
little clinical experience, the concurrent administration of PAXIL CR and
digoxin should be undertaken with caution.

Diazepam

Under steady-state conditions, diazepam does not appear
to affect paroxetine kinetics. The effects of paroxetine on diazepam were not
evaluated.

Procyclidine

Daily oral dosing of immediate-release paroxetine (30 mg
once daily) increased steady-state AUC0-24, Cmax, and Cmin values of
procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively,
compared to procyclidine alone at steady state. If anticholinergic effects are
seen, the dose of procyclidine should be reduced.

Beta-Blockers

In a study where propranolol (80 mg twice daily) was
dosed orally for 18 days, the established steady-state plasma concentrations of
propranolol were unaltered during coadministration with immediate-release
paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol
on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing
Reports).

Theophylline

Reports of elevated theophylline levels associated with
immediate-release paroxetine treatment have been reported. While this
interaction has not been formally studied, it is recommended that theophylline
levels be monitored when these drugs are concurrently administered.

Fosamprenavir/Ritonavir

Co-administration of fosamprenavir/ritonavir with
paroxetine significantly decreased plasma levels of paroxetine. Any dose
adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive Therapy (ECT)

There are no clinical studies of the combined use of ECT
and PAXIL CR.